Recent evidence has implicated neuropeptide Y (NPY) in modulating neurobiological responses to ethanol. Indeed, the presence of this peptide has been shown to influence the amount of ethanol an animal will willingly consume or self-administer. Preliminary evidence also suggests that NPY is involved in the development of ethanol-induced locomotor sensitization, a phenomenon in which repeated drug exposure results in a persistent, enhanced locomotor response. This hyper-sensitized response, thought to result from neuroadapations in the mesolimbic dopaminergic pathway, is hypothesized to reflect enhanced drug craving exhibited by addicts. A separate line of research has shown that drugs of abuse can effect epigenetic changes, including chromatin remodeling via histone acetylation, within this circuitry. These changes impact gene expression without modifying underlying DNA sequences. For example, an increase in acetylation of core histones within the chromatin complex enhances gene expression, while a decrease in acetylation reduces gene expression. In line with these mechanisms, changes in amygdalar NPY expression have been correlated with changes in histone acetylation during withdrawal from chronic ethanol exposure. Thus behavioral sensitization has been closely linked with reward pathways implicated in addiction, and epigenetic modifications and NPY signaling have been shown to exert their effects within these same regions. Until now, the possible relationship between these important mechanisms has remained unexplored. Therefore, the experiments outlined in this proposal are designed to test the guiding hypothesis that ethanol-induced behavioral sensitization is modulated by NPY in regions of the mesolimbic dopaminergic pathway, and that levels of NPY within these regions are in turn mediated by chromatin remodeling via acetylation of core chromatin histones. The first specific aim will examine NPY and acetylated histone immunoreactivity in brain regions implicated in sensitization in both DBA/2J and C57BL/6J mice, two strains with known differences in sensitivity to the locomotor stimulant effects of ethanol. This aim will also determine if enhancement of global histone acetylation with Trichostatin A (TSA), a potent histone deacetylase inhibitor, will augment both locomotor activity and NPY immunoreactivity in these strains. Specific aim 2 will further characterize the interaction between histone acetylation and NPY in the acquisition of behavioral sensitization by assessing the ability of TSA to augment sensitization in mutant mice lacking NPY or the NPY Y1 receptor, or in mice pre- treated with a Y1 receptor antagonist. Finally, specific aim 3 will use site-directed infusion of TSA into the shell of the nucleus accumbens to more clearly define the mechanism by which histone acetylation and NPY modulate ethanol-induced behavioral sensitization. Results of the proposed studies will thus provide an understanding of underlying neural mechanisms of ethanol-induced locomotor sensitization;this in turn may provide insight into potential therapeutic targets aimed at the treatment of alcohol abuse and alcoholism. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating illness, affecting millions of people and their families each year and costing billions of dollars annually in healthcare expenditures, loss of productivity, and related costs. Repeated use of a drug such as alcohol is thought to cause neuroadaptations in key brain circuitry, leading to a hyper-sensitized behavioral response and reflecting the increased drug craving and seeking exhibited by addicts. Results from the proposed research may provide insight into these underlying neuroadaptions stemming from repeated exposure to ethanol, thus providing insight into potential therapeutic targets aimed at the treatment of alcohol abuse and alcoholism.